Process for reducing reflex tachycardia in the treatment of hypertension employing a combination of a diazacyclopentene derivative and a pyridazinone derivative

ABSTRACT

The invention relates to a pharmaceutical product for the treatment of hypertension and thromboembolic diseases containing (+)- or (-)-2-[2,6-dichlorophenoxy) -ethyl]-1, 3-diazacyclopent 2-ene hydrochloride and 4,5-dihydro-6-(4-(I-imidazolyl)-phenyl] -5-methyl-3(2H)-pyridazinone or 4,5-dihydro-6- [4-(I-imidazolyl)- thien-2-yl]- 5-methyl-3 (2H)-pyridazinone as the active substances, process for producing the same, and the use of the combination of active substances for the preparation of medicaments for the treatment of hypertension and thromboembolic diseases.

This is a division of application Ser. No. 705,668, filed Feb. 26, 1985,now U.S. Pat. No. 4,661,487, dated Apr. 28, 1987.

The invention relates to a new process for the treatment of hypertensionand thromboembolic diseases in humans comprising administering to thehuman suffering from such state or disease a medicament containing (±)-or (-)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-enehydrochloride, on the one side, and in combination therewith, a compoundof the formula I ##STR1## wherein A denotes 1,4-phenylene or 2,4- or2,5-thienylene, on the other side, as the active constituents.

The therapy of hypertension with substances which exert their action,above all, via peripheral vasodilation, which is associated with reflextachycardia, is known. Besides the known products employed inhypertension therapy, that is to say hydralazine, dihydralazine andminoxidil, the hypotensive, platelet aggregation-inhibiting andantithrombotic 4,5-dihydro-3(2H)-pyridazinones of the formula I alsoshow this side effect.

It has now been found that the undesired reflex increase is heart ratecan be reduced, avoided entirely or even partly reversed intobradycardia when one of the compounds of the formula I is combined with(±)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-enehydrochloride (German Patent Specification No. 1,795,843, generic name:lofexidine) or(-)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-enehydrochloride (German Offenlegungsschrift No. 3,149,009, generic name:laevlofexidine), which are known as antihypertensives, theantihypertensive effect in some cases being increased further andlasting longer. The platelet aggregation-inhibiting and antithromboticaction of the compounds of the formula I is not reduced by thiscombination.

Thus, the present invention is directed to a process for the treatmentof hypertension and thromboembolic diseases in humans comprisingadministering to the human suffering from such state or disease amedicament containing as active principle a combination of a memberselected from the group consisting of (±)- and(-)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-enehydrochloride, on the one side, and a compound of the formula I, whereinA is a member selected from the group consisting of the 1,4-phenylene,2,5-thienylene and 2,4-thienylene groups, on the other side.

Particularly suitable 4,5-dihydro-3(2H)-pyridazinones of the formula Iin the combinations according to the invention are:4,5-dihydro-6-[4-(1-imidazolyl)-phenyl]-5-methyl-3(2H)-pyridazinone,4,5-dihydro-6-[4-(1-imidazolyl)-thien-2-yl]-5-methyl-3(2H)-pyridazinoneand4,5-dihydro-6-[5-(1-imidazolyl)-thien-2-yl]-5-methyl-3(2H)-pyridazinone,in particular4,5-dihydro-6-[4-(1-imidazolyl)-phenyl]-5-methyl-3(2H)-pyridazinone and4,5-dihydro-6-[4-(1-imidazolyl)thien-2-yl]-5-methyl-3(2H)-pyridazinone.

Pharmaceutically acceptable salts of the compounds of the formula I withinorganic or organic acids are also included, for example and inparticular the hydrochlorides, methanesulphonates, sulphates, acetates,fumarates, benzoates and citrates.

The compounds of the formula I are mentioned in GermanOffenlegungsschrift DE-OS No. 3,212,304, and in published Europeanpatent application EP No. 75,436, and they can be prepared by processesdescribed therein or analogous thereto.

The medicament combinations according to the invention contain theparticular compound of the formula I and (±)-lofexidine or(-)-lofexidine in a weight ratio of 500:1 to 10:1, preferably in a ratioof 150:1 to 30:1. The present invention also relates to pharmaceuticalproducts which contain the active compound combinations according to theinvention or pharmaceutically useful acid addition salts thereof. Thepharmaceutical products according to the invention are those forenteral, such as oral or rectal, and parenteral administration, whichcontain the pharmaceutical active compound combination by itself ortogether with a customary pharmaceutically usable excipient. Thepharmaceutical formulation of the active compound combination isadvantageously in the form of individual doses which are matched to thedesired administration, such as, for example, tablets, coated tablets,capsules, suppositories, granules, solutions, emulsions or suspensions.

The pharmaceutical products according to the present invention areproduced in usual manners by mixing the active substances in the aboveweight ratio with the pharmaceutically usable excipients for the desiredform of administration and converting this mixture into the desired formof administration.

The dosage of the active compound combination is usually between 1 to500 mg per dose, preferably between 3 to 150 mg per dose in the case oforal administration, and can be administered once or several times,preferably two or three times, daily.

The pharmacological advantages of the active compound combinationsaccording to the invention are illustrated in more detail by thefollowing examples.

EXAMPLE 1

Hypotensive and heart rate-modifying action of the combination of4,5-dihydro-6-[4-(1-imidazolyl)-phenyl]-5-methyl-3(2H)-pyridazinone (B)and lofexidine (A) on SHR rats.

Method

The substances were administered orally with a probang to fastingspontaneously hypertensive rats. The animals were fasted 17 hours beforethe start of the experiment.

All the substances were dissolved in 1% strength carboxymethylcellulose(MH 300), and the administration volume was 10 ml/kg.

The starting values of the blood pressure and heart rate were recordeddirectly before the administration. The action of the substance wasmeasured 1, 2, 4, 7 and 24 hours after the administration.

The measurement was performed non-invasively with a W+W Recorder 8002,it being possible to measure the systolic blood pressure and the heartrate. The animals were offered food again 4 hours after administrationof the substance. The values can be seen from Table 1, page 5.

                                      TABLE 1                                     __________________________________________________________________________    Dosage                                                                        (mg/kg) p.o.                                                                  of substance  Δ after administration of the substance                   A  B  Starting value                                                                        1      2       4       7       24 hours                         __________________________________________________________________________    Systolic blood pressure (mmHg)                                                0.1                                                                              -- 221.0 ± 12.5                                                                       -18.8 ± 16.6                                                                       -4.0 ± 18.6                                                                       -11.8 ± 23.2                                                                       -10.8 ± 26.9                                                                       --                               1.0                                                                              -- 231.0 ± 16.9                                                                       -28.4 ± 13.1                                                                      -22.8 ± 11.8                                                                       -23.6 ± 15.5                                                                       -22.2 ± 17.4                                                                       --                               -- 10.0                                                                             210.0 ± 4.6                                                                        -95.4 ± 3.4                                                                       -97.2 ± 4.6                                                                        -98.4 ± 5.6                                                                        -93.0 ± 5.6                                                                        -35.8 ± 6.6                   0.1                                                                              10.0                                                                             213.0 ± 15.5                                                                       -99.4 ± 11.4                                                                      -102.8 ± 11.9                                                                      -105.6 ± 10.9                                                                      -105.0 ± 15.4                                                                      -59.8 ± 7.6                   1.0                                                                              10.0                                                                             246.0 ± 18.4                                                                       -87.2 ± 6.6                                                                       -83.8 ± 13.9                                                                       - 109.2 ± 14.7                                                                     -126.6 ± 13.4                                                                      -120.8 ± 26.4                 Heart rate (beats/minute)                                                     0.1                                                                              -- 357 ± 10                                                                           +10 ± 13                                                                          +37 ± 27                                                                           +12 ± 12                                                                           -14 ± 12                                                                           --                               1.0                                                                              -- 353 ± 11                                                                           -22 ± 8                                                                            -6 ± 13                                                                            -2 ± 15                                                                           -10 ± 16                                                                           --                               -- 10.0                                                                             354 ± 13                                                                           +113 ± 14                                                                         +108 ± 10                                                                          +85 ± 21                                                                           +129 ± 24                                                                          +16 ± 16                      0.1                                                                              10.0                                                                             422 ± 17                                                                           -19 ± 22                                                                          -42 ± 23                                                                           -56 ± 18                                                                           -44 ± 22                                                                           -10 ± 16                      1.0                                                                              10.0                                                                             410 ± 17                                                                           -133 ± 9                                                                          -144 ± 16                                                                          -148 ± 21                                                                          -134 ± 25                                                                           +2 ± 32                      __________________________________________________________________________

EXAMPLE 2

Hypotensive and heart rate-modifying action of the combination of4,5-dihydro-6-[4-(1-imidazolyl)thien-2-yl]-5-methyl-3(2H)-pyridazinone(C) and lofexidine (A) on SHR rats. The experiment was carried out bythe same method as in Example 1, and the values can be seen in Table 2.

                                      TABLE 2                                     __________________________________________________________________________    Dosage                                                                        (mg/kg) p.o.                                                                  of substance  Δ after administration of the substance                   A  C  Starting value                                                                        1      2       4       7                                        __________________________________________________________________________    Systolic blood pressure (mmHg)                                                0.1                                                                              -- 211.0 ± 12.5                                                                       -18.8 ± 16.6                                                                       -4.0 ± 18.6                                                                       -11.8 ± 23.2                                                                       -10.8 ± 26.9                          1.0                                                                              -- 231.0 ± 16.9                                                                       -28.4 ± 13.1                                                                      -22.8 ± 11.8                                                                       -23.6 ± 15.5                                                                       -22.2 ± 17.4                          -- 10.0                                                                             185.0 ± 3.5                                                                        -48.1 ± 16.2                                                                      -66.2 ± 9.9                                                                        -93.9 ± 6.8                                                                        -98.9 ± 9.1                           0.1                                                                              10.0                                                                             182.6 ± 10.1                                                                       -58.8 ± 9.4                                                                       -55.0 ± 9.4                                                                        -71.0 ± 12.3                                                                       -11.6 ± 13.9                          1.0                                                                              10.0                                                                             221.2 ± 10.1                                                                       -91.0 ± 12.4                                                                      -103.0 ± 11.9                                                                      -111.6 ± 10.9                                                                      -73.0 ± 12.2                          Heart rate (beats/minute)                                                     0.1                                                                              -- 357 ±  10                                                                          +10 ± 13                                                                          +37 ± 27                                                                           +12 ± 12                                                                           -14 ± 12                              1.0                                                                              -- 353 ± 11                                                                           -22 ± 18                                                                           -6 ± 13                                                                            -2 ± 15                                                                           -10 ± 16                              -- 10.0                                                                             389 ± 13                                                                           +104 ± 21                                                                         +91 ± 10                                                                           +70 ± 12                                                                           +36 ± 13                              0.1                                                                              10.0                                                                             396 ± 15                                                                           +71 ± 8                                                                           +41 ± 13                                                                           +61 ± 13                                                                           +17 ± 22                              1.0                                                                              10.0                                                                             367 ± 9                                                                            +24 ± 29                                                                          +17 ± 16                                                                           +10 ± 24                                                                           +60 ± 35                              __________________________________________________________________________

EXAMPLE 3

Inhibition of the collagen-induced aggregation of human platelets by thecombination of4,5-dihydro-6-[4-(1-imidazolyl)-thien-2-yl]-5-methyl-3(2H)-pyridazinonehydrochloride (D) with lofexidine (A).

The inhibition of collagen-induced platelet aggregation in vitro wascarried out by the method of Born (Nature, 194, 927-929 (1962)) onplatelet-rich human plasma with4,5-dihydro-6-[4-(1-imidazolyl)-thien-2-yl]-5-methyl-3(2H)-pyridazinonehydrochloride (D), lofexidine (A) and with mixtures of A and D.

The concentration for a half-maximum inhibition (IC₅₀) of thecollagen-induced platelet aggregation was determined as a comparablemeasurement parameter. In each case the mean value of 4 independentdeterminations has been given. In the investigations of the mixtures,the concentration of A was constant at 1×10⁻⁵ mole/l. The results aresummarised in Table 3.

                  TABLE 3                                                         ______________________________________                                        Substance [mole/l]                                                            A              D         % inhibition                                         ______________________________________                                        1 × 10.sup.-5                                                                          0          3                                                   0              4.6 × 10.sup.-8                                                                   50                                                   1 × 10.sup.-5                                                                          5.2 × 10.sup.-8                                                                   50                                                   ______________________________________                                    

EXAMPLE 4

Pharmaceutical form of the combination according to the invention:

Tablets weighing 150 mg with an active compound content of 0.05 mg ofthe imidazoline compound and 5 mg of the pyridazine compound.

(±)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-enehydrochloride: 0.003 kg

4,5-dihydro-6-[4-(1-imidazolyl)-thien-2-yl]-5-methyl-3(2H)-pyridazinone:0.300 kg

Avicel: 7.287 kg

citric acid: 1.200 kg

Aerosil: 0.120 kg

magnesium stearate: 0.090 kg

What we claim is:
 1. Process for reducing reflex tachycardia occurringin the treatment of hypertension and thromboembolic diseases in humanswith compounds of formula I ##STR2## wherein A is a member selected fromthe group consisting of the 2,5-thienylene and 2,4-thienylene groups,comprising administering to the humans an effective amount of acombination of the compound of formula I and a compound selected fromthe group consisting of (±)- and(-)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-enehydrochloride in a weight ratio of from 150:1 to 10:1.
 2. The process asclaimed in claim 1, wherein the weight ratio is 100:1 to 30:1.